Variant: NM_004360.4(CDH1):c.1679C>G (p.Thr560Arg)

CA10577547

234554 (ClinVar)

Gene: CDH1

Condition: CDH1-related diffuse gastric and lobular breast cancer

Inheritance Mode: Autosomal dominant inheritance

UUID: 89320d2b-848b-4794-bcc3-84d990e99660

Approved on: 2023-08-29

Published on: 2023-08-29

HGVS expressions

NM_004360.4:c.1679C>G
NM_004360.4(CDH1):c.1679C>G (p.Thr560Arg)
NC_000016.10:g.68819393C>G
CM000678.2:g.68819393C>G
NC_000016.9:g.68853296C>G
CM000678.1:g.68853296C>G
NC_000016.8:g.67410797C>G
NG_008021.1:g.87102C>G
ENST00000261769.10:c.1679C>G
ENST00000261769.9:c.1679C>G
ENST00000422392.6:c.1496C>G
ENST00000562836.5:n.1750C>G
ENST00000566510.5:c.*345C>G
ENST00000566612.5:c.1566-2608C>G
ENST00000611625.4:c.1742C>G
ENST00000612417.4:c.1679C>G
ENST00000621016.4:c.1679C>G
NM_004360.3:c.1679C>G
NM_001317184.1:c.1496C>G
NM_001317185.1:c.131C>G
NM_001317186.1:c.-254-2608C>G
NM_004360.5:c.1679C>G
NM_001317184.2:c.1496C>G
NM_001317185.2:c.131C>G
NM_001317186.2:c.-254-2608C>G

Pathogenic

• Met criteria codes: PS3 PS4 PP3 PP1_Strong PM2_Supporting

• Not Met criteria codes: BS2 BS1 BS4 BS3 BP5 BP7 BP4 BP3 BP1 BP2 PVS1 PS1 PS2 PP2 PP4 BA1 PM6 PM1 PM3 PM5 PM4

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1

Evidence submitted by expert panel

CDH1 VCEP

The c.1679C>G (p.Thr560Arg) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There are at least 3 in silico predictors in agreement that this variant affects splicing (PP3). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 27880784). Additionally, the variant was found to co-segregation with disease in multiple affected family members, with >7 meioses observed across at least 4 families (PP1_Strong; PMID: 27880784, 29769627). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 27880784, 29769627, 23709761 and SCV000580704.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PP3, PS3, PP1_Strong, PS4.

Met criteria codes

• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Four published families plus internal lab data (SCV000580704.2)
• PP3: Predicted splicing variant. Splicing analysis shows the potential altering of splices sites through the activation of new cryptic donor and acceptor sites and the creation of an ESS site.
• PP1_Strong: Total of 8 segregations across 4 families
• PM2_Supporting: Absent from controls in gnomAD

Not Met criteria codes

• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: Predicted splicing variant. Splicing analysis shows the potential altering of splices sites through the activation of new cryptic donor and acceptor sites and the creation of an ESS site.
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PVS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP4: Shows multiple family members with the CDH1 mutation and all 3 have gastric cancer
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline